Structural Features of 1,3,4-Thiadiazole-Derived Ligands and Their Zn(II) and Cu(II) Complexes Which Demonstrate Synergistic Antibacterial Effects with Kanamycin

Abstract

Classical synthetic protocols were applied for the isolation of three novel 1,3,4-thiadiazole derivatives which were then complexed with the biologically important Cu(II) and Zn(II) ions. All free ligands and their corresponding complexes were characterized using a number of spectroscopic techniques including Ultraviolet-visible (UV–vis), Fluorescence, Infrared (FT-IR), tandem liquid chromatography-mass (LC-MS), X-ray diffraction (XRD), and Nuclear Magnetic Resonance (NMR) spectroscopy (1H, 13C, HSQC, HMBC). The results obtained are consistent with the formation of dihydrate complexes, in which the chelation of the metal ion occurs via one of the thiadiazole nitrogen atoms and the deprotonated hydroxyl group of the neighboring resorcynyl moiety. The Zn(II) complexes utilize a 1:1 ligand–metal ratio, while in the Cu(II) complexes the ligand–metal ratio is 2:1. Although the antibacterial testing identified moderate activity of the compounds against the tested bacterial strains and additionally modest antioxidant activity, a strong synergistic antibacterial effect against Staphylococcus aureus, using concomitant treatment of thiadiazole derivatives with the commercial antibiotic kanamycin, was observed. The most active thiadiazole derivative demonstrated a minimal inhibitory concentration (MIC) of 500 μg/mL while it was 125 μg/mL in the presence of kanamycin. Moreover, in the presence of few thiadiazole derivatives the MIC value of kanamycin decreased from 0.39 μg/mL to 0.5 μg/mL. The antioxidant activity (IC50) of the most active thiadiazole derivative was determined as 0.13 mM which was nearly three-fold lower compared to that of TROLOX (0.5 mM).

Novel Coumarin-Thiadiazole Hybrids and Their Cu(II) and Zn(II) Complexes as Potential Antimicrobial Agents and Acetylcholinesterase Inhibitors

“…These results are consistent with the IR spectra (Section 2.2), which suggest the presence of additional water molecules. Moreover, in the context of the ligand:metal ratio, there is a similarity between Cu(II) complexes 6-9 and those previously reported by our group [20,29], which support the hypothesis that the Cu(II) complexes 6-9 consist of two coumarin-thiadiazole hybrid ligands bound to one central Cu(II) ion with the coordination bonds formed via lone pairs of electrons coming from the deprotonated phenolic group and the nearest (in space) thiadiazole nitrogen. Additionally, the coordination sphere is filled most likely with four water molecules, which in turn enables the variety of coordination numbers (from 4 up to 8).…”

“…In the case of Zn(II) complexes, the lactone band is notably broader, most likely due to the overlap with the C=O stretching band of the acetate, except in complex 12 (Supplementary Figure S2), in which the lactone C=O band remains unaffected. related to the formation of coordination bonds are present between 550-450 cm −1 [27,29]. As expected, the complex formation either does not affect the positioning of the lactone C=O band or only the slight shifts are observed.…”

New Antimicrobial Strategies Based on Metal Complexes

“…A second manner to associate metal complexes with antimicrobials is to exploit existing antimicrobial compounds as ligands for metal cations. Indeed, as shown in a lot of the previous examples [32,72,73,77,78,80,84,86,87,97,175,176], the metal complexes displayed higher activity than their ligands or their building-blocks themselves. It is therefore suggested that metal-antibiotic combinations could lead to synergistic effects in terms of their respective antimicrobial properties.…”

“…This is better than the ligand alone (2.39 mM and 4.78 mM), but much higher than current antibacterials like kanamycin, which demonstrates MICs of 8.05 and 16.10 µ M with respect to the two bacterial strains. Only one of these two zinc complexes was tested together with kanamycin against S. aureus; this induced the fall of their respective MICs, which became 0.34 mM for the thiadiazole-zinc complex, and 1.03 µ M for the kanamycin [78]. Thus, rather than perform antimicrobial assays directly on new compounds, it is sometimes interesting to use them as cofactors of known antibiotics to determine their synergistic effects.…”

“…As discussed in some examples of this review, metal complexes sometimes display higher antimicrobial activity than the standard antimicrobials, particularly against resistant bacteria such as S. aureus MRSA [32,119,156,161,185]. Therefore, it could be interesting to administer the metal complex together with an antimicrobial to improve both of their effects [32,78]. When they do not have the same targets, this multi-therapy approach leads to reaching the bacteria independently on both ends.…”